Tau is a microtubule-associated protein (MAP) involved in microtubule dynamics and maintenance (Amos & Schlieper (2005) Adv. Protein Chem. 71:257-298), and insoluble filamentous tau aggregates form in Alzheimer's disease (AD) and several other neurodegenerative tauopathies (Gamblin et al. (2003) Biochemistry 42:15009-15017). Despite the strong positive correlation between the appearance of filamentous tau and neuronal dysfunction (Binder et al. (2005) Biochim. Biophys. Acta 1739:216-223), no toxic mechanism has been directly tied to these structures, and as a result the molecular basis of tau filament toxicity remains a subject of debate (King (2005) Biochim. Biophys. Acta 1739:260-267).
In AD, degenerating neurons exhibit alterations in synaptic function (Bell, et al. (2006) Eur. J. Pharmacol. 545:11-21; Yoshiyama, et al. (2007) Neuron 53:337-351), the appearance of neuritic varicosities, and the mislocalization of various membrane-bound organelles (MBOs), all of which indicate that intracellular transport is disrupted in this disease (Morfini, et al. (2002) Neuromol. Med. 2:89-99)(Morfini, et al. (2009) J. Neurosc. 29(41):12776-86). Given these observations, and the central role of tau in AD pathology, the effects of monomeric tau on microtubule-dependent fast axonal transport (FAT) has been investigated. Reports have been published arguing that supraphysiological levels of soluble tau can reduce anterograde FAT by interfering with the attachment of the molecular motor kinesin (Ebneth, et al. (1998) J. Cell Biol. 143:777-794; Seitz, et al. (2002) EMBO J. 21:4896-4905; Vershinin, et al. (2007) Proc. Natl. Acad. Sci. USA 104:87-92). However, there is no evidence that such levels of tau are seen in normal or pathological neurons. Further, functional experiments in isolated squid axoplasm (Morfini, et al. (2007) J. Neurosci. Res. 85(12):2620-30) and mice (Yuan, et al. (2008) J. Neurosci. 28(7):1682-7) do not support such an idea. Remarkably, even though the hallmark of AD and other tauopathies is the presence of intracellular tau filaments, the biological effects of filamentous tau on FAT have not been assessed.